The TCR and Transgenic Mouse Development Core will use our expertise in creating animal models of CD4 T cells and human disease to develop state of the art systems to study the role of CD4 T cells during viral infections and detrimental immune-mediated pathology. Core 0 will have several objectives. First, in collaboration with Dr. Welsh, Project 1, we will determine the role of TCR-pMHC affinity in provoking activated CD4 T cells to be targeted by NK cells. With Dr. Swain, Project 2, we will produce and characterize a panel of CD4 T cells specific for influenza A (lAV). These T cells will be used to understand which CD4 T cells are activated during anti-viral immunity, and will also be used with Dr. Stern, Core B to identify novel viral epitopes and to aid in the development of virus-specific pMHC class II tetramers. lAV specific TCRs will be cloned and a novel set of transgenic mice expressing anti-viral TCRs will be created. These new virus-specific TCR Tg mice will be used by Projects 1, 2, and 3 to study anti-viral T cell responses. In collaboration with Dr. Swain and Dr Stern, we will evaluate the role of TCfR-pMIHC affinity in CD4 T cell lineage differentiation and function following lAV infection. We have extensive experience generating T cell hybridomas, cloning TCRs and producing TCR Tg mice. Additional experiments with Dr. Selin, Project 3, will identify mechanisms that cause of cross-reactive CDS T cells to become pathogenic. Experiments with Dr. Selin and Dr. Stern, Projects 3 and 4, will use our- TCR cloning methods and T cell expression systems to characterize human TCRs specific for lAV and HHV-6. The final objective of Core C is to minimize duplicate breeding programs by centralizing the breeding of TCR Tg mice.